This document summarizes safety data from the LORHEN registry on anti-TNF-α treatments in rheumatoid arthritis patients. It found that 18.2% of patients discontinued treatment due to adverse events, with serious infections occurring in 6.9% of patients. Risk of discontinuation due to adverse events increased with age and higher corticosteroid doses. The risk of serious infections was highest for infliximab. The study provides valuable real-world safety data on anti-TNF-α treatments from a large observational registry.

1. Anti TNF-α in Rheumatoid Arthritis
TNF-
safety data from the LORHEN registry
Carlomaurizio Montecucco
Cattedra ed Unità Operativa di Reumatologia
Università degli Studi di Pavia
Fondazione IRCCS Policlinico San Matteo,
Pavia

2. Interpretation of Studies
• Randomised controlled phase III trials
– comparison of two treatments (usually active drug vs. placebo)
in a selected, relatively small, population, over a short period of
time, and usually funded and managed by drug companies
• Observational studies
– “real life” studies in large cohorts of unselected patients over
longer periods and usually less dependent of drug companies
– long term safety and efficacy of a drug in everyday practice
– survival on treatment: good indicator of a drug performance
(combination of safety, efficacy, and other real life factors)

3. Studied Population
• Patients from the Lorhen database
– RA (ARA criteria), active, refractory to traditional DMARDs and
treated with at least one dose of anti-TNF-α
• Follow-up between 6 and 36 months
• Discontinuations within the first 6 months also included
in the data analysis (intention-to treat-approach)
• Only the first course of therapy (switches not included)

4. LOmbardy RHEumatology Network
Patients
Etanercept No follow- excluded from
N=249 up N=50 the analysis
(22,4%) N=5
Adalimumab Lorhen Efficacy
N=332 Register analisys
(29,8%) N=1114
N=1010
Infliximab Discontinua Safety
N=533 tion or AE analyses
(47,8%) N=54 N=1064
6 months
Number of the
patients fulfilling
the minimum criteria
for the analysis
N=1005
Caporali R et al. Autoimm Rev 2008

5. Demographics
All pts Infliximab Adalimum. Etanerc. p
1064 519 (48.8%) 303 (28.5%) 242 (22.7%)
Age (years) 55.84±12.96 55.72±12.07 56.07±13.11 55.81±14.57 ns
Females 885 (83.2%) 423 (81.5%) 258 (85.1%) 204 (84.3%) ns
Males 179 (16.8%) 96 (18.5%) 45 (14.9%) 38 (15.7%) ns
Disease dur. 9.44±7.29 9.28±7.00 9.56±7.90 9.63±7.11 ns
(yrs)
DAS28 5.90±0.97 6.01±0.94 5.68±0.96 5.93±1.02 .000
DI-HAQ 1.46±0.61 1.61±0.61 1.25±0.54 1.41±0.63 .000

6. Demographics
All pts Infliximab Adalimum. Etanerc.
1064 519 (48.8%) 303 (28.5%) 242 (22.7%) p
RF positive 810 (76.1%) 417 (80.3%) 214 (70.6%) 179 (74.0%) .001
Comorbidity 657 (61.7%) 316 (60.9%) 179 (59.1%) 162 (66.9%) ns
Func. class III 317 (29.0%) 186 (35.8%) 63 (20.8%) 68 (28.1%) .000
Methotrexate 899 (84.5%) 499 (96.1%) 226 (74.6%) 174 (71.9%) .000
Corticosteroid 896 (84.2%) 459 (80.7%) 233 (76.9%) 204 (84.3%) .000

7. Survival on Treatment
Favalli EG et al Ann NY Acad Sci 2009

8. Survival on Treatment
Treatment discontinuation
1,0
0,9
0,8
Survival
0,7
0,6 Any cause
Inefficacy
0,5 Adverse event
Other
0,4
0 6 12 18 24 30 36 Months
At risk 1064 924 746 585 482 353 247
Total events 0 120 218 294 331 374 405

9. Discontinuations: Timinig
• Mean time on therapy at discontinuation:
all patients: 13.01±9.78 months
inefficacy group: 14.07±9.97 months
adverse event group: 12.26±10.17 months

10. Discontinuations: Adverse Events
All patients Infliximab Adalimumab Etanercept
Adverse event 194 (18.2%) 106 (20.4%) 60 (19.8%) 28 (11.6%)
Serious infection 73 (6.9%) 42 (8.1%) 20 (6.6%) 11 (4.5%)
Malignancy 18 (1.7%) 6 (1.2%) 8 (2.6%) 4 (1.7%)
Skin or infusion
58 (5.5%) 48 (9.2%) 8 (2.8%) 2 (0.8%)
reaction
Death 13 (1.2%) 3 (0.6%) 5 (1.7%) 5 (2.1%)
Other 32 (3.0%) 6 (1.2%) 19 (6.3%) 7 (2.9%)
Percentages are referred to all patients of that specific group

11. Deaths
Suggested
Patient’s age Days on
Cause of death Drug relation to
at death (yrs) therapy
therapy
Myocardial infarction etanercept 74.0 5 none
Heart failure adalimumab 48.2 30 likely
Aortic aneurysm
etanercept 73.0 197 none
rupture
Stroke infliximab 61.9 314 unlikely
Myocardial infarction infliximab 68.9 363 unlikely
Atlo-epistrofic surgery adalimumab 65.5 380 none
Stroke adalimumab 76.5 536 unlikely

12. Deaths
Suggested
Patient’s age Days on
Cause of death Drug relation to
at death (yrs) therapy
therapy
Myocardial infarction etanercept 77.6 578 unlikely
Pancreatic cancer adalimumab 68.7 587 unlikely
Septicaemia infliximab 65.0 873 certain
Aortic aneurysm
etanercept 70.5 909 unlikely
rupture
Septicaemia adalimumab 77.8 921 certain
Post-infective
etanercept 57.0 980 likely
cerebritis

13. Risk of Discontinuation
All causes Adverse events
AHR AHR
(95% CI) p (95% CI) p
For 10 yrs 1.07 1.20
Age (0.98-1.17) .150 (1.05-1.37) .009
more
1.04 1.25
Sex Male (0.78-1.39) .777 (0.83-1.88) .287
Dis. dur. <5 years 1 1
0.97 1.07
5-10 yrs (0.74-1.28) .846 (0.72-1.61) .736
0.82 1.00
>10 years (0.62-1-08) .162 (0.67-1.50) .991

14. Risk of Discontinuation
All causes Adverse events
AHR AHR
p p
(95% CI) (95% CI)
N. previous 2 1 1
DMARDs
1.39 0.74
3 .013 .164
(1.07-1.81) (0.49-1.13)
1.62 1.31
≥4 .001 .163
(1.22-2.14) (0.90-1.90)
Corticost. No 1 1
1.03 1.07
≤5 mg/day .837 .775
(0.76-1.40) (0.67-1.70)
1.57 2.13
>5 mg/day .015 .005
(1.09-2.26) (1.26-3.60)
MTX 0.53 0.68
Yes .000 .113
(0.38-0.75) (0.42-1.10)
Comorb. 0.80 0.69
Yes .055 .032
(0.64-1.01) (0.50-0-97)

15. Risk of Discontinuation
All causes Adverse events
AHR AHR
(95% CI) p (95% CI) p
N. tender For 1 joint 1.04 1.04
joints more (1.01-1.07) .013 (0.99-1.09) .096
N. swoll. For 1 joint 1.01 0.99
joints more (0.98-1.03) .555 (0.96-1.03) .692
DI-HAQ For 0.3 points 0.99 1.08
more (0.92-1.06) .745 (0.97-1.20) .147
DAS28 For 0.6 points 0.84 0.82
more (0.71-0.99) .033 (0.64-1.04) .095
ESR (mm/h) For 10 points 1.14 1.12
more (1.07-1.21) .000 (1.02-1.23) .017

16. Factors Associated with
Discontinuation
• Age: adverse events
• N. DMARDs ≥4: inefficacy
• Steroid >5 mg/day: adverse events
• No MTX: inefficacy
• Absence of comorbidity: adverse events
• ESR (10 points): inefficacy + adv. events

17. Discontinuations: Adverse Events
All patients
Adverse event 194 (18.2%)
Serious infection 73 (6.9%)
Malignancy 18 (1.7%)
Skin or infusion
58 (5.5%)
reaction
Death 13 (1.2%)
Other 32 (3.0%)

18. DMARDS and infections in RA
• Increased risk in RA vs non-RA (RR 1.33)
Doran MF et al Arthritis Rheum 2002
• Factors associated with higher risk
– Age
– Extraarticular disease
– Rheumatoid factor
– ESR
– Cyclophosphamide
– Corticosteroids
• MTX not associated with a significant risk
Caporali R et al Autoimm Rev 2008

19. SERIOUS INFECTIONS IN LORHEN STUDY
Favalli EG et al. Autoimm Rev 2009

20. Incidence rate of serious infections during
anti-TNF treatment for RA in real life
(x1000 pts/year)
• LORHEN1 35.9
• BSRBR2 53.2
• French study3 105 (34 before anti-TNF)
1) Favalli EG et al. Autoimm Rev 2009
2) Dixon W et al. Arthritis Rheum 2006
3) Salliot C et al Rhematology 2007

21. TB reactivation during TNF blockade
MONITORNET 9 cases / 8787 p-y
LORHEN 5 cases / 2069 p-y

22. Discontinuations: Adverse Events
All patients
Adverse event 194 (18.2%)
Serious infection 73 (6.9%)
Malignancy 18 (1.7%)
Skin or infusion
58 (5.5%)
reaction
Death 13 (1.2%)
Other 32 (3.0%)

23. The background rates of malignancy
in RA
Symmons D PM, Silman AJ. Arthritis Rheum2004

24. Crude incidence rate of malignancies in
two Italian registries
N°of p-y N°/
cases 1000 p-y
LORHEN
4 2069 1.93
NHL
MONITORNET 6 8787 0.69
OTHER LORHEN 14 2069 6.76
MALIGNANCIES
MONITORNET 24 8787
2.73

25. Cancer type Observed Expected SIR (95% CI)
a)
Lymphomas^ 4 0.80 4.98 (1.34-12.74)
Hematologic* 5 1.23 4.07 (1.31-9.49)
Solid** 13 15.33 0.85 (0.45-1.45) SIRs of cancer in RA
Overall 18 16.56 1.09 (0.64-1.72) patients treated with
TNF blockers in
Cancer type Observed Expected SIR (95% CI) comparison with
b) Lymphomas^ 4 0.67 5.99 (1.61-15.35)
general population
Hematologic* 5 1.23 4.08 (1.32-9.53)
living in Milan (a) and
Solid** 13 17.99 0.72 (0.38-1.24)
Varese (b).
Overall 18 19.22 0.94 (0.55-1.48)

26. Evaluation of risk of cancer in RA patients included in the LORHEN study.
Results of a multivariate analysis.
100
10
AHR and 95% CI
1
0,1
Age Male No* 0-5 mg >5 mg No* MTX
Corticosteroids DMARDs association

27. Severe adverse event
Safety according to age 1,0
0,9
SOPRAVVIENZA CUMULATIVA
Discontinuation rate for AEs in 0,8
pts >65 years old vs younger pts
0,7
Age
<65 yrs
0,6
65+ yrs
Hazard Ratio=1.49 0,5
0,4
0 6 12 18 24 30 36
18<age<65 Age ≥65
p
(n= 771) (n=293)
282/771 123/293
Total discontinuations (36.6%) (42%)
0,043 Severe infections
Due to AEs
130/771 64/293
0,017
(10%) p=0.0042
(16.9%) (21.8%)
Due to inefficacy
129/771
(16.7%)
51/293
(17.4%)
0,591 Malignancies
23/771 8/293 (3,7%) p=0.004
Due to other causes (3%) (2.7%)
0,932
Filippini M et al Clin Rev Allergy Immunol. 2009

28. Conclusions
• In an Italian cohort of more than 1000 patients
with long-standing RA refractory to traditional
DMARDs, the 3-year expected survival rate on
anti-TNF therapy was about 53%
• Adverse events and inefficacy were equally
responsible for drug discontinuation, although
during the first year they were more frequently
due to adverse events
• Serious infection was the most frequent
adverse event responsible for drug
discontinuation, followed by infusion or skin
reaction

29. Conclusions
• Etanercept showed the best retention
rate but the design of the study did not
allow a comparison of the three drugs
• Increasing age, corticosteroid dose >5
mg/day and absence of comorbidity
were associated with a significantly
higher risk of therapy discontinuations
because of adverse events

30. Conclusions
• Can we do better?
– concomitant MTX (or other DMARD ?) in all
cases
– corticosteroid dose as low as possible
– anti-TNF as second line agent
– optimization of infusion procedures
– infection alert: correct TB screening, close
follow-up and monitoring